Himbacine is a piperidine alkaloid, which was isolated from Galbulimima baccata being one species of pinaceous plant and the structure of which was determined in 1956, and, as the structural characteristics thereof, three points of condensation of 5-membered lactone ring to thermodynamically stable transdecalin ring in cis configuration, eight asymmetric centers including four internuclear hydrogens, and further binding of 3-cyclic portion with piperidine ring via trans double bond can be mentioned. 
In recent years, the senile dementia represented by Alzheimer type dementia has posed a significant problem socially and a substantial therapeutic drug therefore is desired earnestly. As one of approaches, from a phenomenon of decreased function of central cholinergic nerve in demential patients, development of therapeutic drugs based on so-called xe2x80x9ccholine hypothesisxe2x80x9d is being advanced actively. Roughly classifying them, it is possible to divide into four below. Namely, they are (1) inhibitor of taking-in of choline, (2) inhibitor of acetylcholinesterase, (3) activator for synthesizing choline acetyltransferase and (4) compound acting on muscarine receptor (muscarine M1 against or M2 receptor antagonist). It has become clear recently that the himbacine exhibits potent and selective antagonistic action on M2 receptor that is considered to suppress the release of nerve terminal acetylcholine, hence the potential as an antidemential drug has been found.
As described, the himbacine is a globally noteworthy compound from two points of potent activity and interesting chemical structure and, in recent years, its syntheses are reported by some groups. Thereamong, overall syntheses having intramolecular Diels-Alder reaction as a key reaction in all cases have been accomplished by groups of Kozikowski et al and Chackalamannil et al (Kozikowski, A. P. et al, J. Am. Chem. Soc., 1995, 117, 9369. Chackalamannil, S. et al, J. Am. Chem. Soc., 1996, 118, 9812). With these processes using intramolecular Diels-Alder reaction, however, there are problems of not only necessity for passing through troublesome processes in the synthesis of its skeleton, but also difficult synthesis of affinous compounds that become important for aiming at improved activity and decreased side effect. While, if using intermolecular Diels-Alder reaction, required constitutional units can be synthesized separately and each can be combined arbitrarily to react, thereby leading to easy synthesis of affinous compounds. However, its is the status quo that the synthesis of himbacine having such intermolecular Diels-Alder reaction as a key reaction has not yet been accomplished.
As a result of diligent studies in view of the subjects aforementioned, the inventors have found that the following inventive compounds are useful as the intermediates in the preparation of himbacine using the intermolecular Diels-Alder reaction as a key reaction, leading to the completion of the invention.
Namely, the invention provides hydronaphtho[2,3-c]furan derivatives represented by a following general formula (1) 
(wherein R1 denotes a lower alkyl group or substituted or unsubstituted aralkyl group, R2 denotes a hydrogen atom, lower alkyl group or substituted or unsubstituted aralkyl group, R3 and R4 unitedly denote an oxygen atom or methylene group, or R3 denotes a hydrogen atom and R4 denotes a hydroxyl group, lower alkoxy group, substituted or unsubstituted aralkyloxy group or lower acyloxy group, R5 and R6 unitedly denote an oxygen atom, or R5 denotes a hydrogen atom and R6 denotes a hydroxyl group, lower alkoxy group, substituted or unsubstituted aralkyloxy group or lower acyloxy group, and, in the case of broken lines accompanied, one denotes single bond and the other denotes double bond, or both denote single bonds), hydronaphtho[2,3-c]furan derivatives represented by a following general formula (1-1) 
(wherein R1 denotes a lower alkyl group or substituted or unsubstituted aralkyl group, R2 denotes a hydrogen atom, lower alkyl group or substituted or unsubstituted aralkyl group, R3 and R4 unitedly denote an oxygen atom or methylene group, or R3 denotes a hydrogen atom and R4 denotes a hydroxyl group, lower alkoxy group, substituted or unsubstituted aralkyloxy group or lower acyloxy group, and in the case of broken lines accompanied, one denotes single bond and the other denotes double bond, or both denote single bonds), hydronaphtho[2,3-c]furan derivatives represented by a following general formula (1-2) 
(wherein R1 denotes a lower alkyl group or substituted or unsubstituted aralkyl group, R2 denotes a hydrogen atom, lower alkyl group or substituted or unsubstituted aralkyl group, R3 and R4 unitedly denote an oxygen atom or methylene group, or R3 denotes a hydrogen atom and R4 denotes a hydroxyl group, lower alkoxy group, substituted or unsubstituted aralkyloxy group or lower acyloxy group, and R7 denotes a hydrogen atom, lower alkyl group, substituted or unsubstituted daralkyl group or lower acyl group), hydronaphtho[2,3-c]furan derivatives represented by a following general formula (2) 
(wherein R1 denotes a lower alkyl group or substituted or unsubstituted aralkyl group, R2 denotes a hydrogen atom, lower alkyl group or substituted or unsubstituted aralkyl group, R7 denotes a hydrogen atom, lower alkyl group, substituted or unsubstituted aralkyl group or lower acyl group), and R8 denotes a hydrogen atom or protective group of hydroxyl group), and hydronaphtho[2,3-c]furan derivatives represented by a following general formula (3) 
(wherein R1 denotes a lower alkyl group or substituted or unsubstituted aralkyl group, R2 denotes a hydrogen atom, lower alkyl group or substituted or unsubstituted aralkyl group, and, in the case of broken line accompanied, it denotes single bond or double bond), and a process for preparing compounds represented by a following general formula (3a) 
(wherein R1 denotes a lower alkyl group or substituted or unsubstituted aralkyl group, and R2 denotes a hydrogen atom, lower alkyl group or substituted or unsubstituted aralkyl group), characterized by reacting compounds represented by a following general formula (4) 
(wherein R1 denotes a lower alkyl group or substituted or unsubstituted aralkyl group), with compounds represented by a following general formula (5) 
(wherein R2 denotes a hydrogen atom, lower alkyl group or substituted or unsubstituted aralkyl group).
In the invention, for xe2x80x9clower alkylsxe2x80x9d, straight chain or branched ones with carbon atoms of 1 to 6 such as methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl and 2-methylpropyl are mentioned and it doesn""t matter whether saturated or unsaturated. For xe2x80x9caralkyl groupsxe2x80x9d, benzyl group, 1-phenylethyl group, etc. are mentioned and, as substituents, lower alkyl group, lower alkoxy group, halogen atom, cyano group, nitro group, etc. are mentioned. For xe2x80x9clower alkoxy groupxe2x80x9d, straight chain or branched ones with carbon atoms of 1 to 6 such as methoxy, ethoxy, 1-methylethoxy, 1,1-dimethylethoxy, propoxy and 2-methylpropoxy are mentioned and it doesn""t matter whether saturated or unsaturated. For xe2x80x9caralkyloxy groupsxe2x80x9d, benzyloxy group, 1-phenylethoxy group, etc. are mentioned and, as substituents, lower alkyl group, lower alkoxy group, halogen atom, cyano group, nitro group, etc. are mentioned. For xe2x80x9clower acyl groupsxe2x80x9d, ones with carbon atoms of 1 to 6 such as formyl group, acetyl group, propionyl group and 2,2-dimethylpropionyl group are mentioned, and, for xe2x80x9clower acyloxy groupsxe2x80x9d, ones with carbon atoms of 1 to 6 such as formyloxy group, acetoxy group, propionyloxy group and 2,2-dimethylpropionyl group are mentioned. Moreover, for the protective groups of hydroxyl group, trialkylsilyl groups such as trimethylsilyl group and t-butyldimethylsilyl group, arylmethyl groups such as benzyl group and diphenylmethyl group, acyl groups such as acetyl group and propionyl group, lower alkoxymethyl groups such as methoxymethyl group and ethoxymethyl group, aralkyloxymethyl groups such as benzyloxymethyl group, tetrahydropyranyl group, and the like are mentioned, and the introduction and elimination thereof can be performed by appropriately adopting the methods described in the literature (Green, T. W.; Wuts, P. G. M. xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 2nd Ed., Wiley Interscience Publication, John-Weiley and Sons, New York, 1991, pp 14-118).
The compounds of said general formula (4) can be prepared by publicly known processes (Beckmann, M. et al, Tetrahedron: Asymmetry, 1990, 1, 335 etc.). Similarly, the compounds of general formula (5) can be prepared by publicly known processes (Spencer, T. A. et al, J. Am. Chem. Soc., 1973, 95, 250 etc.). Besides the inventive compounds have a plurality of asymmetric carbon atoms and corresponding optical isomers can exist, but these optical isomers and their mixtures are to be included in the invention.
The compounds represented by general formula (1) and (2) in the invention can be prepared according to following preparative processes, making the compounds represented by said general formula (3a) synthesizable from the compounds represented by said general formula (4) and (5) as key intermediates. 
(First process)
This process is for preparing 4,9-epoxyoctahydronaphtho[2,3-c]furan-1(3H)-one derivatives represented by said general formula (3a) by adding 4,5,6,7-tetrahydroisobenzofuran represented by said general formula (5) to (S)-5-lower alkyl-2(5H)-furanone represented by said general formula (4).
This reaction can be conducted in the presence or absence of Lewis acid such as zinc chloride, zinc bromide, zinc iodide, boron trifluoride, aluminum chloride, tin tetrachloride, boron trifluoride-diethyl ether complex or lithium perchlorate, rhodium complex such as Wilkinson""s complex, sodium dodecylsulfate or cetyltrimethyl ammonium bromide. The reaction is conducted in the presence or absence of, for example, hydrocarbonic solvent such as pentane, hexane, cyclohexane, benzene, toluene or xylene, halogenated hydrocarbonic solvent such as dichloromethane, 1,2-dichloroethane, chloroform or carbon tetrachloride, ethereal solvent such as diethyl ether, tetrahydrofuran or 1,4-dioxane, aprotic polar solvent such as acetonitrile, propionitrile, nitromethane, nitroethane, N,N-dimethylformamide or dimethyl sulfoxide, or mixed solvent of one of these with water, and usually proceeds smoothly at xe2x88x9220xc2x0 C. to 200xc2x0 C. Also, as the case may be, stabilizers like radical eliminator such as 2,6-di-t-butyl-4-methylphenol (BHT), etc. may be added.
(Second process)
This process is for catalytically reducing the double bond in 4,9-epoxyoctahydronaphtho[2,3-c]furan-1(3H)-one derivatives represented by said general formula (3a), obtainable in the first process aforementioned, to prepare 4,9-epoxyoctahydronaphtho[2,3-c]furan-1(3H)-one derivatives represented by said general formula (3b).
This reaction is conducted usually in solvent, using catalyst such as palladium-carbon, Raney nickel, palladium hydroxide, rhodium-alumina or platinum oxide. As a solvent, any can be used, if it doesn""t take part in the reaction, but, for example, hydrocarbonic solvent such as pentane, hexane, cyclohexane, benzene, toluene, or xylene, halogenated hydrocarbonic solvent such as dichloromethane, 1,2-dichloroethane, chloroform or carbon tetrachloride, ethereal solvent such as diethyl ether, tetrahydrofuran or 1,3-dioxane, alcoholic solvent such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol or 2-methyl-2-propanol, or mixed solvent of one of these with water is used preferably. The reaction proceeds smoothly at 0xc2x0 C. to 100xc2x0 C. under 101.3 KPa to several hundreds KPa.
(Third process)
This process is for cutting the ether bond of 4,9-epoxydecahydronaphtho[2,3-c]furan-1(3H)-one derivatives represented by said general formula (3b), obtainable in the second process aforementioned, to prepare octahydronaphtho[2,3-c]furan-1(3H)-one derivatives represented by said general formula (1-1a).
This reaction can be conducted usually in the presence of suitable reactant, for example, alkali metal alkoxide such as sodium methoxide or sodium ethoxide, alkali metal organic base such as n-butyl lithium, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide, tertiary organic base such as triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, imidazole, pyrrolidine, piperidine, 1,5-diazabicyclo[4.3.0]nona-5-ene or 1,8-diazabicyclo[5.4.0]ude-7-cene, or Lewis acid such as zinc chloride, zinc bromide, zinc iodide, boron trifluoride, aluminum chloride, tin tetrachloride, boron trifluoride-diethyl ether complex or lithium perchlorate. As a solvent, any can be used, if it doesn""t take part in the reaction, but, for example, hydrocarbonic solvent such as pentane, hexane, cyclohexane, benzene, toluene or xylene, halogenated hydrocarbonic solvent such as dichloromethane, 1,2-dichloroethane, chloroform or carbon tetrachloride, or ethereal solvent such as diethyl ether, tetrahydofuran or 1,4-dioxane is used preferably. The reaction proceeds smoothly at xe2x88x92110xc2x0 C. to 100xc2x0 C.
(Fourth process)
This process is for isomerizing the double bond of octahydronaphtho[2,3-c]furan-1(3H)-one derivatives represented by said general formula (1-1a), obtainable in the third process aforementioned, using a suitable base, to prepare octahydronaphtho-[2,3-c]furan-1(3H)-one derivatives represented by said general formula (1-1b).
This reaction can be conducted in the presence of, for example, alkali metal alkoxide such as sodium methoxide or sodium ethoxide, alkali metal organic base such as n-butyl lithium, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide, or tertiary organic base such as triethylamine, diisopropylethylamine, pyridine, N-methyl-morpholine, imidazole, pyrrolidine, piperidine, 1,5-diazabicyclo-[4.3.0]nona-5-ene or 1,8-diazabicyclo[5.4.0]unde-7-cene. As a solvent, any can be used, if it doesn""t take part in the reaction, but, for example, hydrocarbonic solvent such as pentane, hexane, cyclohexane, benzene, toluene or xylene, halogenated hydrocarbonic solvent such as dichloromethane, 1,2-dichloroethane, chloroform or carbon tetrachloride, ethereal solvent such as diethyl ether, tetrahydrofuran or 1,4-dioxane, or alcoholic solvent such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol or 2-methyl-2-propanol is used preferably. The reaction proceeds smoothly at xe2x88x92110xc2x0 C. to 100xc2x0 C.
(Fifth process)
This process is for catalytically reducing the double bond in octahydronaphtho[2,3-c]furan-1(3H)-one derivatives represented by said general formula (1-1b), obtainable in the fourth process aforementioned, to prepare decahydronaphtho[2,3-c]furan-1(3H)-one derivatives represented by said general formula (1-1c).
This reaction is conducted usually in solvent, using catalyst such as palladium-carbon, Raney nickel, palladium hydroxide, rhodium-alumina or platinum oxide. As a solvent, any can be used, if it doesn""t take part in the reaction, but, for example, hydrocarbonic solvent such as pentane, hexane, cyclohexane, benzene, toluene or xylene, halogenated hydrocarbonic solvent such as dichloromethane, 1,2-dichloroethane, chloroform or carbon tetrachloride, ethereal solvent such as diethyl ether, tetrahydrofuran or 1,4-dioxane, alcoholic solvent such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol or 2-methyl-2-propanol, or mixed solvent of one of these with water is used preferably. The reaction proceeds smoothly at 0xc2x0 C. to 100xc2x0 C. under 98.1 KPa to several hundreds KPa. Besides, when using platinum oxide for catalyst, only single isomer can be obtained selectively.
(Sixth process)
This process is for reducing the lactonecarbonyl bond in decahydronaphtho[2,3-c]furan-1(3H)-one derivatives represented by said general formula (1-1c), obtainable in the fifth process aforementioned, and further for protecting 1-hydroxyl group of 1,4-dihydroxy-dodecahydronaphtho[2,3-c]furan derivatives produced by selective alkylation, to prepare 1-alkoxy-4-hydroxy-dodecahydronaphtho[2,3-c]furan derivatives represented by said general formula (1-2a).
The reduction of this reaction is conducted by using dialkylaluminum hydride such as diisobutylaluminum hydride. As a solvent, any can be used, if it doesn""t take part in the reaction, but, for example, hydrocarbonic solvent such as pentane, hexane, cyclohexane, benzene, toluene or xylene, halogenated hydrocarbonic solvent such as dichloromethane, 1,2-dichloroethane, chloroform or carbon tetrachloride, or ethereal solvent such as diethyl ether, tetrahydrofuran or 1,4-dioxane is used. The reaction proceeds smoothly at xe2x88x92100xc2x0 C. to 100xc2x0 C. The etherification of 1-position hydroxyl group to be conducted successively is performed in alcohol solvent in the presence of a suitable Lewis acid. As the xe2x80x9csuitable Lewis acidxe2x80x9d, for example, zinc chloride, zinc bromide, zinc iodide, boron trifluoride, aluminum chloride, tin tetrachloride, boron trifluoride-diethyl ether complex, lithium perchlorate or the like is mentioned, and, as the alcohol solvent, for example, alcoholic solvent such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol or 2-methyl-2-propanol is used preferably. The reaction usually proceeds smoothly at xe2x88x92100xc2x0 C. to 100xc2x0 C.
Moreover, the introduction of aralkyl group or acyl group to 1-position hydroxyl group to be conducted successively is performed according to publicly known methods (Green, T. W.; Wuts, P. G. M. xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 2nd Ed., Wiley Interscience Publication, John-Weiley and Sons, New York, 1991, pp 46-66 and pp 87-118).
(Seventh process)
This process is for oxidizing the 4-position hydroxyl group in 4-hydroxydodecahydronaphtho[2,3-c]furan derivatives represented by said general formula (1-2a), obtainable in the sixth process aforementioned, to prepare 4-oxo-dodecahydronaphtho[2,3-c]furan derivatives represented by said general formula (1-2b).
As the oxidizing agent to be used in this process, chromic acid, chromic trioxide-pyridine mixed system, dimethyl sulfoxide-oxalyl chloride-triethylamine mixed system, ruthenium complex, Dess-Martin reagent or the like can be used. The oxidation is usually preferable to be conducted in solvent and, for example, halogenated hydrocarbonic solvent such as dichloromethane, 1,2-dichloroethane, chloroform or carbon tetrachloride is used. The reaction proceeds smoothly at xe2x88x92100xc2x0 C. to 100xc2x0 C.
(Eighth process)
This reaction is for conducing Wittig reaction by reacting ylide prepared from methyltriphenylphosphonium salt and base, with 4-position carbonyl group in 4-oxo-dodecahydronaphtho[2,3-c]furan derivatives represented by said general formula (1-2b), obtainable in the seventh process aforementioned, to prepare 4-methylenedodecahydronaphtho[2,3-c]furan derivatives represented by said general formula (1-2c).
As the phosphonium salt to be used in this process, for example, methyltriphenylphosphonium chloride, methyltriphenylphosphonium bromide or methyltriphenylphosphonium iodide is mentioned, and the reaction can be conducted in the presence of, for example, alkali metal alkoxide such as sodium methoxide or sodium ethoxide, alkali metal organic base such as n-butyl lithium, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide or potassium bis(trimethylsilyl)amide, or tertiary organic base such as triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, imidazole, pyrrolidine, piperidine, 1,5-diazabicyclo[4.3.0]non-5-ene or 1,8-diazabicyclo[5.4.0]undec-7-ene as a base to be used. As a solvent, any can be used, if it doesn""t take part in the reaction, but, for example, hydrocarbonic solvent such as pentane, hexane, cyclohexane, benzene, toluene or xylene, halogenated hydrocarbonic solvent such as dichloromethane, 1,2-dichloroethane, chloroform or carbon tetrachloride, ethereal solvent such as diethyl ether, tetrahydrofuran or 1,4-dioxane, or alcoholic solvent such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol or 2-methyl-2-propanol is used preferably. The reaction proceeds smoothly at xe2x88x92110xc2x0 C. to 100xc2x0 C.
(Ninth process)
This reaction is for conducting hydroboraton and oxidation reaction to 4-position methylene group in 4-methylene-dodecahydronaphtho[2,3-c]furan derivatives represented by said general formula (1-2c), obtainable in the eighth process aforementioned, to prepare 4-hydroxymethyl-dodecahydronaphtho[2,3-c]furan derivatives represented by said general formula (2a).
As a hydroborating agent to be used in this reaction, for example, borane-tetrahydrofuran complex, borane-dimethyl sulfide complex, 9-borabicyclo[3,3,1]nonane or the like is mentioned and, as a solvent, any can be used, if it doesn""t take part in the reaction, but, for example, hydrocarbonic solvent such as pentane, hexane, cyclohexane, benzene, toluene or xylene, halogenated hydrocarbonic solvent such as dichloromethane, 1,2-dichloroethane, chloroform or carbon tetrachloride, ethereal solvent such as diethyl ether, tetrahydrofuran or 1,4-dioxane, or mixed solvent thereof is used. The reaction proceeds smoothly at xe2x88x92110xc2x0 C. to 200xc2x0 C. In the oxidation reaction to be conducted next, aqueous hydrogen peroxide, m-chloroperbenzoic acid, peracetic acid or the like is used. As a solvent, any can be used, if it doesn""t take part in the reaction, but, for example, hydrocarbonic solvent such as pentane, hexane, cyclohexane, benzene, toluene or xylene, halogenated hydrocarbonic solvent such as dichloromethane, 1,2-dichloroethane, chloroform or carbon tetrachloride, ethereal solvent such as diethyl ether, tetrahydrofuran or 1,4-dioxane, alcoholic solvent such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 2-methyl-1-propanol or 2-methyl-2-propanol, or mixed solvent of one of these with water is used preferably. The reaction proceeds smoothly at xe2x88x92110xc2x0 C. to 100xc2x0 C.
The 4-hydroxy-dodecahydronaphtho[2,3-c]furan derivatives represented by said general formula (2a), synthesized through the synthetic processes as described above are derived to 4-phenylsulfonylmethyl-decahydronaphtho[2,3-c]furan derivatives by sulfonation of 4-position hydroxymethyl group, substitution of 4-position sulfonyloxymethyl group with phenylthio group, and oxidation of 4-position phenylthiomethyl group to phenylsulfonylmethyl group, according to the synthetic method of Kozikowski et al (Kozikowski, A. P. et al, J. Am. Chem. Soc., 1995, 117, 9369) (see Referential example 1).
Furthermore, the inventors confirmed that, by using 4-phenylsulfonylmethyl-decahydronaphtho[2,3-c]furan derivatives obtained as optically active substances and converting these according to the method described in literature (Kozikowski, A. P. et al, J. Am. Chem. Soc., 1995, 117, 9369), natural type himbacine could be synthesized (see Referential examples 2 through 4).